Project Summary/Abstract Alzheimer?s disease (AD) is the most dominant form of dementia characterized by deposition of extracellular amyloid plaques and neurofibrillary tau tangles. For decades, neurobiologists have focused on these two major pathological hallmarks for potential therapeutic intervention. More recently, neuroinflammation the third major pathological hallmark of AD has garnered attention following the genome-wide association studies that identified several loci harboring genetics variants influencing inflammatory pathways in AD. Since then, there has been an intense research focused on microglia, the resident macrophages of the central nervous system (CNS), that have led to a better understanding of their role in AD. However, the contribution of astrocytes, the predominant inflammatory cell in the CNS, in AD development has remains largely unknown. Given that there is a need for a better understanding of the role of astrocytes in AD, we propose to test the hypothesis that reactive astrocytes facilitates tauopathy and amyloidosis by increasing neuroinflammation. In this regard, we previously discovered that chronic activation of the astrocytic ?2-Na/K ATPase (?2-NKA) pump, promoted neurodegeneration in a mouse model of amyotrophic lateral sclerosis. In preliminary data, we demonstrates an enrichment of the astrocytic ?2-NKA in a mouse model of tauopathy and in a mouse model of amyloidosis. Moreover, the ?2-NKA is elevated in patients with both AD and progressive supranuclear palsy, a primary tauopathy. The enrichment of the astrocytic ?2-NKA appears to be critical for tau pathogenesis as pharmacological inhibition of the ?2-NKA with the cardiac glycoside digoxin in a tauopathy mouse model prevented the accumulation of pathological tau. Similarly, the pharmacological inhibition of the ?2-NKA in a mouse model for amyloidosis attenuated the astrocytic responsiveness to plaques, which significantly decreased plaque burden and dystrophic neurites. Our proposed studies aim to test our hypothesis by determining the extent to which inhibiting the ?2-NKA is neuroprotective, evaluating the effects of knocking out the ?2-NKA, and identifying a mechanism by which the astrocytic ?2-NKA facilitates amyloid burden and tau pathogenesis. These results will clarify the contribution of reactive astrocytes in AD, identify an astrocytic pathophysiological mechanism that facilitates tau/A? pathogenesis, and potentially provide an alternative target for therapeutic intervention.